Conjugate Addition of Amines to an r,β-Unsaturated Imine Derived from r-Aminophosphonate. Synthesis of γ-Amino-r-dehydroaminophosphonates Javier Vicario, Domitila Aparicio, and Francisco Palacios* Departamento de Quı´mica Orga´nica I, Facultad de Farmacia, UniVersidad del Paı´s Vasco, Apartado 450, 01080 Vitoria, Spain
[email protected] ReceiVed October 2, 2008
Aza-Michael reaction of ammonia, aliphatic, aromatic and optically active amines to an R,β-unsaturated imine derived from R-aminophosphonate affords R-dehydroaminophosphonates with a γ-stereogenic center bearing an amino group. Resulting γ-amino R-dehydroaminophosphonates can be used for the preparation of phosphorylated pyrimidine derivatives.
The aza-Michael reaction is one of the most powerful reactions in organic chemistry for the formation of C-N bonds.1 Its simplicity makes it the most appropriate alternative for the preparation of functionalized γ-amino compounds. Conjugate addition of nitrogen nucleophiles to Michael acceptors can sometimes proceed without catalyst,2 but, very often, deprotonation of the amine,3 or activation of the conjugated system by the presence of Bro¨nsted4 or Lewis5 acids or organocatalysts6 is required, especially in the case of the addition of weakly nucleophilic aromatic amines. Despite the fact that conjugate addition of amines to R,β-unsaturated carbonylic compounds (1) (a) For reviews, see: Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992. (b) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633. (c) Vicario, J. L.; Badı´a, D.; Carrillo, L.; Etxebarria, J.; Reyes, E.; Ruiz, N. Org. Prep. Proc. Int. 2005, 37, 513. (2) Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141. (b) Kumar, R.; Chaudhary, P.; Nimesh, S.; Chandra, R. Green Chem. 2006, 356. (3) (a) Some recent examples of aza-Michael using lithium amides: Sakai, T.; Doi, H.; Kawamoto, Y.; Yamada, K.-I.; Tomioka, K. Tetrahedron Lett. 2004, 45, 926. (b) Etxebarria, J.; Vicario, J. L.; Badia, D.; Carrillo, L.; Ruiz, N. J. Org. Chem. 2005, 70, 8790. (c) Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Rodriguez-Solla, H.; Smith, A. D. Chem. Commun. 2006, 2664. (d) Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71, 4706. (4) (a) Um, I.-H.; Lee, E.-J.; Min, J.-S. Tetrahedron 2001, 57, 9585. (b) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484. (5) For some recent examples of Lewis acid catalyzed aza-Michael reactions, see: (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319. (b) Varala, R.; Alam, M. M.; Adapai, S. R. Synlett 2003, 720. (c) Azizi, N.; Saidi, R. M. Tetrahedron 2004, 60, 383. (d) Narsaiah, A. V. Lett. Org. Chem. 2007, 4, 462. (e) Bhanushali, M. J.; Nandurkar, N. S.; Jagtap, S. R.; Bhanage, B. M. Catal. Commun. 2008, 9, 1189.
452 J. Org. Chem. 2009, 74, 452–455
is well documented in the literature, to the best of our knowledge there are no examples reported about conjugate addition of amines to R,β-unsaturated imines. Moreover, the presence of a phosphonate group in the imine increases the synthetic interest of these substrates due to the applications of functionalized aminophosphonates in organic and medicinal chemistry.7-10 We have been involved in the chemistry of azabutadienes,11 and we recently reported an efficient synthesis of R,β-unsaturated imines derived from R-aminoesters12a and R-aminophosphonates.12b These 1-azadienes have shown very assorted reactivity, and they have proved to be very useful intermediates for the synthesis of several heterocycles13 as well as for the preparation of R-amino acid or R-aminophosphonic acid derivatives,12 in some cases enantioselectively.14 Following our interest in the chemistry of R-aminophosphonates15 and 1-azabutadienes11,12 and specifically in the reactivity of R,β-unsaturated imines derived from R-aminophosphonates, we report here the first example of a conjugate addition of amine nucleophiles to the β-carbon vinylogously attached to an imine group. Conjugate addition of ammonia 2a (R1 ) R2 ) H) to R,βunsaturated imine 1 derived from R-aminophosphonate does not require any additional activation and can be performed in CH2Cl2 under mild conditions (procedure A, see the Experimental Section), affording exclusively the E isomer of γ-amino-Rdehydroaminophosphonate 3a (R1 ) R2 ) H), in a stereose(6) For some recent examples of organocatalytic aza-Michael reactions, see: (a) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. J. Am. Chem. Soc. 2006, 128, 9328. (b) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1983. (c) Liu, B. K.; Wu, Q.; Qian, X. Q.; Lv, D. S.; Lin, X. F. Synthesis 2007, 2653. (d) Han, X. Tetrahedron Lett. 2007, 48, 2845. (e) Yeom, C.-E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63, 904. (f) Uria, U.; Vicario, J. L.; Badia, D.; Carrillo, L. Chem. Commun. 2007, 2509. (7) For an excellent book, see: Kukhar, V. P., Hadson, H. R., Eds. In Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological ActiVity; J. Wiley: Chichester, 2000. (8) For reviews on R-aminophosphonates, see: (a) Kafarski, P.; Lejczak, B. Curr. Med. Chem: Anti-Cancer Agents. 2001, 1, 301. (b) Gambecka, J.; Kafarski, P. Mini-ReV. Med. Chem. 2001, 1, 133. (9) For reviews on β-aminophosphonates, see: (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. ReV. 2005, 105, 899. (b) Palacios, F.; Alonso, C.; de los Santos, J. M. In EnantioselectiVe Synthesis of β-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley: New York, 2005; p 277. (10) For some recent contributions on γ-aminophosphonates, see: (a) Fernandez, M. C.; Diaz, A.; Guillin, J. J.; Blanco, O.; Ruiz, M.; Ojea, V. J. Org. Chem. 2006, 71, 6958. (b) Chowdhury, S.; Muni, N. J.; Greenwood, N. P.; Pepperberg, D. R.; Standaert, R. F. Bioorg. Med. Chem Lett. 2007, 17, 3745. (c) Hakogi, T.; Monden, Y.; Taichi, M.; Iwama, S.; Fujii, S.; Ikeda, K.; Katsumura, S. J. Org. Chem. 2002, 67, 4839. (11) (a) Palacios, F.; Aparicio, D.; Garcı´a, J.; Rodrı´guez, E.; Ferna´ndezAcebes, A. Tetrahedron 2001, 57, 3131. (b) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J. Org. Lett. 2002, 4, 769. (c) Palacios, F.; Aparicio, D.; Vicario, J. Eur. J. Org. Chem. 2002, 4131. (d) Palacios, F.; Herra´n, E.; Rubiales, G.; Ezpeleta, J. M. J. Org. Chem. 2002, 67, 2131. (e) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J. J. Org. Chem. 2004, 69, 8767. (12) (a) Palacios, F.; Vicario, J.; Aparicio, D. J. Org. Chem. 2006, 71, 7690. (b) Palacios, F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org. Chem. 2007, 72, 2682. (13) (a) Palacios, F.; Vicario, J.; Aparicio, D. Tetrahedron Lett. 2007, 48, 6747. (b) Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem. 2006, 2843. (14) (a) Palacios, F.; Vicario, J. Org. Lett. 2006, 8, 5405. (b) Palacios, F.; Vicario, J. Synthesis 2007, 3923. (15) (a) de los Santos, J. M.; Ignacio, R.; Aparicio, D.; Palacios, F. J. Org. Chem. 2007, 72, 5202. (b) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem. 2005, 70, 8895. (c) Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.; de los Santos, J. M.; Gil, J. I.; Lopez de Munain, R. Tetrahedron: Asymmetry. 2003, 14, 689. (d) Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.; de los Santos, J. M.; Gil, J. I.; Lopez de Munain, R. J. Org. Chem. 2002, 67, 7283.
10.1021/jo8022022 CCC: $40.75 2009 American Chemical Society Published on Web 11/19/2008
SCHEME 1. Nucleophilic Addition of Ammonia and Amines to r,β-Unsaturated Imine 1
SCHEME 2. Pathway for the Formation of E- and Z-Enamines by Addition of Amines to Imine 1
TABLE 1. (E)-γ-Amino r-Dehydroaminophosphonates 3 Synthesized by Aza-Michael Reaction of Ammonia and Amines 2 to Imine 1
entry
compd
1 2 3 4 5 6 7
3a 3b 3c 3d 3e 3f 3g
R1 H H H H
R2
H p-CH3-C6H4 p-NO2-C6H4 CH3 (CH2)4 (S)-methoxymethylpyrrolidinec (S)-pseudoephedrinec
E/Za
% yieldb
100/0 100/0 100/0 100/0 100/0 100/0 100/0
82, 80d 83, 81d 81, 80d 88 79, 77d 86 81
a Determined by integration of 31P NMR signals of the crude. b Yield after chromatography. c er ) 1:1. d Yield using the multicomponent reaction, starting from but-2-(E)-enoylphosphonic acid diethyl ester 10 (procedure B).
lective fashion, with good yield (Scheme 1, Table 1, entry 1). γ-Amino-R-dehydroaminophosphonate 3a was characterized on the basis of its 1H, 31P, and 13C NMR, IR, and MS spectra. For example, the 1H NMR spectrum of (E)-enamine 3a presents a representative double doublet for the enaminic CH at δH ) 6.46 ppm, which shows coupling constants 3JHH ) 8.6 Hz, with the adjacent methyne, and 3JPH ) 13.4 Hz, typical for a cis relative configuration P-H in olefins.16 13C NMR spectrum of (E)enamine 3a shows two doublets for the methyne and the quaternary carbon of the enamine double bond at δC ) 145.9 ppm, with a coupling constant 2JPC ) 23.7 Hz, and at δC ) 128.2 ppm, with a coupling constant 1JPC ) 208.0 Hz, respectively, and another doublet for the methyne at 44.1 ppm with a coupling constant 3JPC ) 15.1 Hz typical for the trans relative configuration P-C in alkenes.16 Aromatic amines showed a similar behavior, and conjugate addition of p-toluidine 2b (R1 ) H, R2 ) p-Me-C6H4) and electron-deficient p-nitrophenylamine 2c (R1 ) H, R2 ) p-NO2C6H4) to R,β-unsaturated imine 1 in CH2Cl2 gave only (E)-γamino-R-dehydroaminophosphonates 3b,c with very good yields (16) (a) Palacios, F.; Ochoa de Retana, A. M., D.; Oyarzabal, J.; Pascual, S.; Ferna´ndez de Troconiz, G. J. Org. Chem. 2008, 73, 4568. (b) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron 1994, 50, 12727. (c) Duncan, M.; Gallager, M. J. Org. Magn. Reson. 1981, 15, 37.
(Scheme 1, Table 1, entries 2 and 3). Likewise, the process was extended to methylamine 2d (R1 ) H, R2 ) Me) (Table 1, entry 4), a secondary cyclic amine such as pyrrolidine (R1R2 ) (CH2)4) (Table 1, entry 5) and optically active β-amino alcohol derivatives such as (S)-methoxymethylpyrrolidine or (S)-pseudoephedrine (Table 1, entries 6 and 7) with the formation the (E)-γ-amino-R-dehydroaminophosphonates 3d-g. The formation of the E-enamines could be explained taking into account a pseudo-trans conformation17 of imine 1. Nucleophilic addition of the amine could initially take place to afford the ionic intermediate I, with a Z configuration of the carbon-carbon double bond. If the γ-amine substituent is adequate, the zwitterionic (Z)-enamine I could evolve to the thermodynamically more stable zwiterionic E-enamine III18 and the corresponding (E)-enamines can be obtained (Scheme 2). A different behavior was observed by the conjugate addition of benzylamine 4a (R1 ) C6H5), allylamine 4b (R1 ) CHdCH2), and propargylamine 4c (R1 ) CtCH) to R,β-unsaturated imine 1 in CH2Cl2 to give (Z)-γ-amino-R-dehydroaminophosphonates19 5a-c in a stereoselective manner (Scheme 1, Table 2 entries 1-3). 1H NMR spectrum of enamine 5a shows the double doublet for the enaminic CH at δH ) 6.11 ppm with coupling constant values 3JHH ) 10.3 Hz with the adjacent methyne and 3JPH ) 41.9 ppm with the phosphonate, representative for a trans relative configuration P-H in the double bond. The 13C NMR spectrum of enamine 5a presents doublets at δC ) 137.8 ppm and δC ) 127.2 ppm, with coupling constants 2 JPC ) 20.3 Hz and 1JPC ) 200.3 Hz, the first one for the methyne and the second one for the quaternary carbon of the enamine double bond as well as another doublet for the (17) The configuration and conformation in solution of R,β-unsaturated imine 1 was established on the basis of 2D NMR experiments. For the nuclear Overhauser enhancement spectroscopy (NOESY) spectrum, see the Supporting Information. (18) Unlike enamine species I, in the iminic structures II there is free rotation around the C-C single bond, and if the energy barrier is small enough, the zwiterionic imine II can be converted into E-enamines III. (19) Z Isomers compared to E-enamines showed a downfield shift of the signal corresponding to enaminic CH and an upfield shift of the signal assigned to the CH in the β-position.
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TABLE 2.
γ-Amino r-Dehydroaminophosphonates 5 and 7
Synthesized
TABLE 3.
Isomerization of Z-Enamines 5a-c and Mixtures of Eand Z-Enamines 7a,b to E-Enamines 3h-k
entry
compd
R1
E/Za
% yieldb
entry
compd
starting enamine
R1
yielda (%)
1 2 3 4 5
5a 5b 5c 7a 7b
C6H5 CHdCH2 CtCH CH2CH3 CH(CH3)2
0/100 0/100 0/100 62/38 63/37
79, 78c 85 91 86 89
1 2 3 4 5
3h 3i 3j 3k 3l
5a 5b 5c 7ab 7bb
C6H5 CHdCH2 CtCH CH2CH3 CH(CH3)2
95 95 94 93 91
a Determined by integration of 31P NMR signals of the crude. b Yield after chromatography c Yield using the multicomponent procedure, starting from but-2-(E)-enoylphosphonic acid diethyl ester 10 (procedure B).
a
Yield after chromatography b Mixtures of E- and Z-enamines.
SCHEME 4. Multicomponent Synthesis of (E)-γ-Amino-r-dehydroaminophosphonates 3
SCHEME 3. Base-Mediated Isomerization of Z-Enamines 5 and 7 to E-Enamines 3
SCHEME 5.
β-methyne at δC ) 51.4 ppm and that shows a coupling constant 3 JPC ) 3.6 Hz representative for a cis relative configuration P-C in the alkene bond.16 The formation of the Z-enamines could be explained by nucleophilic addition of the amine to afford the ionic intermediate I, with a Z configuration of the carbon-carbon double bond (Scheme 2). However, when a primary amine with sp2 (benzyl or allyl amine) or sp (propargyl amine) β-carbon was used, this zwitterionic species I would undergo fast intermolecular interchange of the proton to afford the thermodynamically less favored Z-enamines. On the other hand, when aliphatic amines such as npropylamine 6a (R1 ) CH2CH3) or isobutylamine 6b (R1 ) CH(CH3)2) were treated with R,β-unsaturated imine 1, mixtures of E and Z-enamines 7a,b were obtained (Scheme 1, Table 2, entries 4 and 5). In these cases, n-propyl and isobutyl groups linked to the amino seems to favor the formation of mixtures of E and Z isomers. With these results, we wanted to explore if the isomerization between Z- and E-enamines could be performed. In fact, heating Z-enamines 5a-c in CH2Cl2 and in the presence of triethylamine afforded exclusively E-enamines 3h-j in very good yields (Scheme 3, Table 3, entries 1-3). In a similar way, heating mixtures of E- and Z-enamines 7a,b in CH2Cl2 in the presence of triethylamine gave exclusively E-enamines 3k,l (Scheme 3, Table 3, entries 4 and 5). This thermal isomerization is consistent with the higher stability of E-enamines toward the corresponding Z-enamines. It should be mentioned that the nucleophilic addition of amines to R,β454 J. Org. Chem. Vol. 74, No. 1, 2009
Synthesis of 4,5-Dihydro-2-pyrimidones 11a,b
unsaturated imine 1 does not require the use of the isolated starting material, since the synthesis of enamines 3 can also be performed in very good yields in a multicomponent reaction (Scheme 4, Table 1, entries 1-3 and 5, Table 2, entry 1) by addition to R-ketophosphonate 10 of phosphazene 9, generated “in situ” by addition of trimethylphosphine to p-nitrophenylazide 8, with formation of β,γ-unsaturated iminophosphonate 1 and subsequent addition of the corresponding amine to the reaction mixture (procedure B, see the Experimental Section). Finally, given both the interest of azaheterocyclic phosphonates20 and that it is well-known that molecular modifications involving the introduction of organophosphorus functionalities could increase biological activity,21 enamines 3 were used as synthetic intermediates for the synthesis of 6-membered-ring phosphonylated heterocycles. Treatment of enamines 3h,i at room temperature with triphosgene in the presence of 2 equiv of triethylamine afforded the phosphonylated 4,5-dihydro-2pyrimidones 11a,b in very good yield (87-90%) (Scheme 5). As far as we know, this strategy represents the first synthesis of 4,5-dihydropyrimidin-2-one-containing phosphorus substituents. (20) For an excellent review of azaheterocyclic phosphonates, see: Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. ReV. 2004, 104, 6177. (21) Toy, A. D. F.; Walsh, E. N. In Phosphorus Chemistry in EVeryday LiVing; American Chemical Society: Washington DC., 1987.
In conclusion, we have shown here the first example of an aza-Michael reaction to R,β-unsaturated imines 1 to afford functionalized enamines 3. The fact that a R,β-unsaturated imine derived from R-aminophosphonate is used as Michael acceptors makes this example of aza-Michael a suitable method for the preparation of chiral γ-amino R-dehydro aminophosphonates 3. R-7,8 and γ-aminophosphonate derivatives10 as well as phosphapeptides containing R-aminophosphonic units show a variety of biological activities with interest in medicinal chemistry. Moreover, an application of γ-amino R-dehydro aminophosphonates 3 for the first synthesis of phosphorylated pyrimidone derivatives20 is reported. Experimental Section Representative Example for the Aza-Michael Reaction of Amines 3 with the r,β-Unsaturated Imine-Derived from r-Aminophosphonate 4. Synthesis of [1-(4-Nitrophenylamino)-3-ptolylaminobut-1-enyl]phosphonic Acid Diethyl Ester 3b. Procedure A: To a solution of R,β-unsaturated imine 1 (163 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added p-toluidine (64 mg, 0.6 mmol). The solution was stirred for 30 min, and the resulting mixture was concentrated under reduced pressure. The crude residue was purified by chromatography (SiO2, AcOEt/MeOH 95:5) to afford 178 mg (83%) of 3b as a pale yellow oil. Procedure B: multicomponent reaction procedure starting from but-2-(E)-enoylphosphonic acid diethyl ester 10. To a solution of p-nitrophenyl azide 8 (82 mg, 0.5 mmol) in CH2Cl2 (3 mL) at 0 °C was added a 1.0 M solution of trimethylphosphine in toluene (0.5 mL). The resulting solution was stirred for 30 min until N2 evolution stopped, which indicates the completion of the reaction and phosphazene 9 formation. But2-(E)-enoylphosphonic acid diethyl ester 10 (2.06 g, 10 mmol) was then added, and the reaction was stirred for an additional 30 min at rt. Neat p-toluidine (64 mg, 0.6 mmol) (0.6 mmol) was then
added, and the reaction mixture was stirred for 30 min. The resulting solution was concentrated under reduced pressure, and the resulting yellow oily crude was purified by chromatography (SiO2, AcOEt) to afford 175 mg (81%) of 3b as a pale yellow oil. Rf (AcOEt/ MeOH 95:5): 0.08. 1H NMR (300 MHz, CDCl3): δ 1.11-1.29 (m, 6H, 2 × CH3), 1.35 (d, 3JHH ) 6.8 Hz, 3H, CH3), 3.98-4.09 (m, 4H, 2 × CH2O), 2.21 (s, 3H, CH3), 4.22 (m, 1H, CHN), 6.18 (s, 1H, NH), 6.38 (dd, 3JPH ) 14.2 Hz, 3JHH ) 8.9 Hz, 1H, CH)), 6.77 (d, 3JHH ) 9.0 Hz, 2 × CHar), 6.47 (d, 3JHH ) 8.6 Hz, 2H, 2 × CHar), 6.93 (d, 3JHH ) 8.6 Hz, 2H, 2 × CHar), 8.07 (d, 3JHH ) 9.0 Hz, 2H, 2 × CHar). 13C NMR (75 MHz, CDCl3): δ 16.1 (d,3JPC ) 5.5 Hz, 2 × CH3), 19.6 (CH3), 20.2 (CH3), 47.2 (d, 3JPC ) 15.1 Hz, CHN), 62.5 (d,2JPC ) 6.4 Hz, CH2O), 62.6 (d,2JPC ) 6.1 Hz, CH2O), 113.3 (2 × CHar), 114.5 (2 × CHar), 125.8 (2 × CHar), 126.2 (Cquat), 127.4 (d, 1JPC ) 212.0 Hz), 129.6 (2 × CHar), 139.6 (Cquat), 143.6 (Cquat), 146.8 (d, 2JPC ) 23.1 Hz, CH)), 151.7 (Cquat). 31 P NMR (120 MHz, CDCl3): δ 13.0. FTIR (KBr) νmax (cm-1): 3343 (N-H st), 1239 (P ) O st). CIMS m/z (amu): 433 ([M+ + H], 87), 296 ([M+] - PO(OEt)2, 100). Anal. Calcd for C21H28N3O5P: C, 58.19; H, 6.51; N, 9.69. Found: C, 58.25; H, 6.47; N, 9.73.
Acknowledgment. The present work was supported by the Direccio´n General de Investigacio´n del Ministerio de Ciencia y Tecnologı´a (MCYT, Madrid DGI, CTQ2006-09323) and by the Departamento de Educación Universidades e Investigación del Gobierno Vasco (IT-277-07). J.V. thanks the Ministerio de Ciencia e Innovacio´n for a Ramo´n y Cajal contract. Supporting Information Available: Procedures and full characterization for compounds 3, 5, and 7. This material is available free of charge via the Internet at http://pubs.acs.org. JO8022022
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